Many medical conditions are best treated by administration of a pharmaceutical in such a way as to modify its action over an extended period of time. Modified release form means a formulation which releases the drug not immediately, e.g. after disintegration or in case of enteric-coating, i.e. gastro-resistant coating, after stomach passage, but offers a sustained, retard, continuous, gradual, prolonged or pulsatile release and therefore alters drug plasma levels distinctively versus an immediate release formulation.
Mycophenolic acid (MPA) was first isolated in 1896, and has been extensively investigated as a pharmaceutical of potential commercial interest. It is known to have anti-tumor, anti-viral, immunosuppressive, anti-psoriatic, and anti-inflammatory activity [see e.g. W. A. Lee et al, Pharmaceutical Research (1990), 7, p. 161-166 and references cited therein]. A derivative of MPA such as mycophenolate mofetil (MMF) had been introduced commercially in the US and elsewhere under the brand name CellCept® as an immunosuppressant in the immediate release form for the treatment or prevention of organ or tissue transplant rejection. A pharmaceutical delayed release composition comprising mycophenolate sodium (Myfortic®) has been approved for marketing in the United States. It has been concluded in a study that mycophenolate sodium is therapeutically equivalent to MMF at equimolar MPA doses. 769.4 mg of mycophenolate sodium contains equimolar amounts of MPA compared with 1000 mg of MMF [Progress in Transplantation; June 2004; Gabardi, S et al]. Mycophenolate Sodium salts are known, e.g. in South African Patent 68/4959. U.S. Pat. Nos. 6,025,391, 6,172,107 and 6,306,900 describe pharmaceutical compositions comprising a mycophenolate salt, wherein the composition is enteric coated thereby preventing the release of the mycophenolate salt in the stomach, and releasing the mycophenolate salt in the upper part of the intestinal tract. However the major limitation of formulating such a composition of mycophenolate is that although the enteric coat is intended to prevent release of the drug in the stomach to prevent associated side effects, the clinical study results in 423 de novo kidney allograft recipients indicates that the incidence of GI adverse events was 79.8% with mycophenolate sodium and 77.1% with MMF (P=NS) and also the frequency of dosage reductions, discontinuation, or temporary interruptions of therapy secondary to GI toxicities were comparable. It is well known from the literature that Mycophenolate mofetil (MMF) is a prodrug containing mycophenolic acid (MPA) as the active moiety which is an inhibitor of de novo purine nucleotide synthesis. MMF can cause toxicity, mainly of hematologic and/or gastrointestinal nature (Transplantation, Van Gelder et al., 1999). It has been reported that occurrence of side effects due to MMF is the major reason for reducing the dose of MMF which leads to graft loss. Enteric coated mycophenolate sodium (EC-MPS), the advanced enteric-coated formulation of MPA is the salt mycophenolate sodium, has a delayed release because of the enteric coating and is released in the small intestine. This enteric coated formulation, apart from the above-mentioned issues, is expected to result in an improper and incomplete absorption and/or undesired absorption pattern of the drug that may be achieved since the drug is not getting absorbed from the entire gastro-intestinal tract (GIT), but instead restricted to absorption from only the intestinal region. Table 1 enlists the adverse effects of MMF and EC-MPS in controlled de novo and maintenance renal transplantation studies. There seems to be no significant difference in the side effects on post administration of both, MMF and EC-MPS.
TABLE 1Adverse Events (%) in Controlled de novo and MaintenanceRenal Studies Reported in 20% of PatientsSide effectsMMF (%)MPS (%)Blood and Lymphatic System disorderAnemia21.621.9Leukopenia19.220.5Gastrointestinal System DisordersConstipation38.039.5Nausea29.127.1Diarrhoea24.823.5Vomiting2023Dyspepsia22.519Infections and infestationsUrinary Tract Infection29.133.3CMV infections20.218.1Nervous System DisordersInsomnia23.523.8
The etiology of the observed gastrointestinal effects due to MMF was reviewed by Behrend et al (Adverse Gastrointestinal Effects of Mycophenolate Mofetil Aetiology, Incidence and Management, 2001). It was concluded by the authors that the gastrointestinal adverse effects of MMF were mainly related to Cmax, of the active moiety i.e., MPA whereas the efficacy was related to AUC. A few other authors have also reported that there is a correlation between plasma concentration of MPA (C30) and side effects (Correlation of mycophenolic acid pharmacokinetic parameters with side effects in kidney transplant patients treated with mycophenolate mofetil, Clinical Chemistry, 2001, Mourad et al).
The insignificant difference in the adverse effects of MMF and EC-MPS (Table 1) can be attributed to high Cmax value of MPA in both the cases. The values of Cmax for MMF (1 g b.i.d) and EC-MPS (720 mg b.i.d) were found to be 21.3 and 18.93 μg/mL respectively (Am J Transplant, 2007, Budde et al.). Hence, there still exists an unmet need for developing a suitable dosage form which releases the drug mycophenolate sodium throughout the GIT in a sustained release manner to achieve the desired Cmax with optimum AUC for achieving better patient compliance as extended release dosage form of MPS will have lower Cmax as compared to MMF or EC-MPS and may lead to reduction in side effects.
PCT Publication No. WO2006024479 discloses a composition comprising mycophenolic acid, a salt or a prodrug thereof in a modified release form. Such compositions are intended to improve the drug distribution in the intestine, and to delay the delivery of the drug substance to the intestinal tract. Multiparticulate systems such as granules, pellets, beads and minitablets are disclosed. Also disclosed are coated pellets and granules compressed into rapid disintegrating tablets. However no single unit dosage forms either uncoated or coated for providing a sustained release of mycophenolate sodium particularly throughout the GIT are disclosed. Further the multiparticulate system of the said publication if formulated as a compressed dosage form such as tablet, the application of compression force in a compression machine will lead to rupturing of the coated multiple units resulting in loss of uniformity of the coating layer over the entire unit (pellet or granule) thus producing variable and unpredictable release of the active agent from such compressed forms. Furthermore the multiparticulate system of the present invention lacks patient compliance since the multiple units such as pellets or granules if administered orally to a patient will cause an unpleasant and gritty feeling in the mouth and would be difficult to swallow since it might stick to the oral cavity. Still further, such multiparticulate systems would require the use of an additional taste-masking agent in the composition.
PCT Publication No. WO2005034916 describes a composition comprising mycophenolic acid, a salt or a prodrug thereof in multiparticulate form such that the compositions disintegrate or dissolve in the mouth, stomach or small intestine to give multiparticles, wherein the multiparticles are enteric coated. Such compositions do not provide a uniform sustained release of the active agent throughout the GIT; instead it releases the drug only in the intestine. Further the drug release from the multiparticulate systems are generally non-uniform since it is extremely difficult to predetermine and/or control the behavior of such systems upon in vivo administration.
US Publication No. 20060280795 discloses an enteric coated delivery device for the delayed release of an active agent in the gastrointestinal tract comprising a core comprising an active agent; a first outer coating, comprising a relatively hydrophobic substantially water insoluble polymer having substantially water insoluble hydrophilic particles embedded therein; and a first inner coating layer, comprising an agent that can cause the dissolution of at least one of said water insoluble components of said outer coating, and optionally a water soluble polymer, such that said insoluble particles in said outer coating, upon absorption of liquid, form channels leading to said inner coating layer, thus enabling the dissolution thereof, whereby the agents contained therein are released to cause at least the dissolution, degradation or destruction of said outer coating, and the release of the active agent from the core of said device. Such compositions do not provide a sustained release of the active agent throughout the GIT; instead it releases the drug only in the intestine.
U.S. Pat. No. 5,554,384 discloses high dose pharmaceutical formulation preferably as a capsule comprising a therapeutically effective amount of an active agent selected from the group consisting of mycophenolate mofetil and mycophenolic acid, said active agent having been heated to a first temperature above its melting point, cooled to a second temperature below its melting point at which second temperature said active agent remained liquefied, and filled into a pharmaceutical dosage form while in said cooled liquefied state. However the said patent does not disclose any sustained release composition comprising mycophenolate mofetil and mycophenolic acid; neither does it disclose any compositions comprising a substantially high dose of mycophenolate sodium.
A review of the prior art literature shows that no formulation has been approved till date for a sustained release pharmaceutical composition comprising mycophenolate sodium. Mycophenolate sodium formulations disclosed in prior art are particularly multiparticulate and/or enteric-coated (delayed release) systems which suffer from several disadvantages as discussed earlier. Hence there still exists a need for commercially acceptable preferably single unit dosage forms for oral administration with good patient convenience and acceptance. Also there is still an unmet need to develop especially once-a-day mycophenolate compositions comprising substantially high dose of said active agent for sustained release particularly from a matrix system such that the inter- and intra-patient variability is reduced. Particularly there still exists a need for developing oral mycophenolate sodium compositions which are stable and easily swallowable upon oral administration, possess appreciable bioavailability characteristics, are well-tolerated and safe, and exhibit a drug release for a substantially longer duration. Also there exists a need to develop oral pharmaceutical compositions comprising mycophenolate sodium for prophylactic and/or therapeutic use, which can release the drug in a desired manner such as to maintain therapeutic levels of the drug in the plasma for extended period of time but without causing drug related toxicity, and which can be prepared in an easy and cost-effective manner.
The inventors of the present invention have done extensive research and conducted several experiments to alleviate the drawbacks existing in the prior art to develop dosage form compositions comprising mycophenolate sodium by using different excipients and formulation methods for preferably modifying the release rate of said immunosuppressant so as to obtain the desired in-vitro release characteristics which aids in the interpretation of predictable behavior of the dosage form in-vivo as mentioned earlier. The compositions of the present invention are preferably unit dosage forms which provides prophylactic and/or therapeutic concentration of the active agent for an extended duration of time devoid of any substantial toxicity, thus demonstrating a significant advancement over the prior art. The inventors of the present invention have invented extended release formulations of mycophenolate sodium, characterized in that mycophenolate sodium is released in a sustained manner, alleviating or at least reducing the chances of causing any associated side effects without compromising the bioavailability of active agent. Further, the active agent mycophenolate sodium is well absorbed orally and and/or the variation of its absorbability is substantially alleviated when made into compositions according to the present invention.